Skip to main content

Full text of "Stem cell therapy for neuropathic pain treatment."

See other formats 

■JOmVI/ VUlJ imo.. 

2007; p2 - 11 

Review Article 

Stem cell therapy for neuropathic pain treatment 

Dario Siniscalco*, Francesco Rossi, Sabatino Maione 

'Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", Second University of Naples 

* Dario Siniscalco, Department of Experimental Medicine - Section of Pharmacology "L. Donatelli", Second 
University of Naples. Via S. Maria di Costantinopoli, 16 - 80138 Naples, Italy. E.mail; 

Published online on 14 Nov 2007 


Pain initiated or caused by a primary lesion or dysfunction in the nervous system 
is defined as neuropathic pain. 

About 75 -150 million people in the United States are suffering for chronic pain 
disorder. Neuropathic pain has a great impact on the human wellbeing. It is very 
debilitating and often has an associated degree of depression that contributes to 
decreasing the quality of life. Moreover, the management of chronic pain is 
costly to the health care system. Pain is a national healthcare priority in US: the 
United States Congress has declared the present decade (2001-2010) as the 
"Decade of Pain Control and Research". 

Neuropathic pain is a very complex disease, involving several molecular 
pathways. Due to its individual character, its treatment is extremely difficult. 
Current available drugs are usually not acting on the several mechanisms 
underlying the generation and propagation of pain. 

Nowadays, pain research is focusing on newer molecular ways, such as stem cell 
therapy, gene therapy, and viral vectors for delivery of biologic anti-nociceptive 
molecules. These methods could provide a new therapeutic approach to 
neuropathic pain relief. 

Key words; neuropathic pain, stem cell therapy, gene therapy, virus vector 

Copyright © Journal of Stem cells and Regenerative medicine. All rights reserved 
JSRM/ 003010200002/Nov 14, 2007. 

JSRM/Vol3 No.l, 2007; p 2 -11 


Vol3 Issuel 

Journal of Stem Cells & Regenerative Medicine 

Pathophysiology of Neuropathic Pain 

Neuropathic pain is defined as pain initiated or 
caused by a primary lesion or dysfunction in 
the nervous system [1 ' 2 \ and several clinical 
symptoms are associated with it [3] . Most 
common are hyperalgesia (an increased 
response to a stimulus which is normally 
painful; patients with hyperalgesia perceive 
pain spontaneously) and allodynia (pain as a 
result of a stimulus which does not provoke 
pain; patients with allodynia do not feel 
constant pain, in fact in the absence of a 
stimulus there is no pain) [4] . Neuropathic pain 
can be triggered by central or peripheral nerve 
injury. Changes in the spinal cord or in the 
peripheral nerve, but also in the brain, have 
been reported, although these molecular 
alterations are still far to be clarified. 
Nociceptive signalling terminates in the spinal 
cord, the first centre involved in the 
controlling and processing of pain 
transmission. Indeed, in the dorsal horn of the 
spinal cord nociceptive afferent fibers 
terminate where the nociceptive neurons are 
located in the superficial lamina I (marginal 
layer) and in the lamina II (substantia 
gelatinosa). Interactions between nociceptive 
and non-nociceptive afferent pathways control 
the transmission of nociceptive information to 
higher centres in the brain [5] . 

Due to nociceptive input, such as peripheral 
nerve injury, the spinal cord anatomical 
structure is subjected to a re-organization. 
Indeed, the myelinated primary afferent fibers 
sprout into lamina II of the dorsal horn, 
establishing synaptic contacts with second- 
order neurons. In this way, they help to 
conduct the allodynic transmission [6] . 

Another change is a phenomena called "wind- 
up", a condition of central sensitization 
resulted from severe and persistent injury. In 
this condition, C-fibres are frequently sped on, 
releasing glutamate, and the response of the 
neurons of the dorsal horn spinal cord 
progressively increases [7 ' 81 . 

Glutamate is the major nociceptive excitatory 
neurotransmitter released from A-delta and C- 
fibres. Once released, glutamate is able to 
evoke fast synaptic potentials in dorsal horn 
neurons by activating the pre- and post- 
synaptic glutamate receptors. Among them, 
the ionotropic NMDA receptor is most 
involved in the events correlated with 
nociception [9], and with the maintenance of 
central sensitization and hyperexcitability of 
dorsal horn neurons. Activation of NMDA 
receptors increases the concentration of the 
calcium ion by the indirect activation of 
protein kinase C [10] . 

In the brain, the insular cortex is directly 
involved in the pain modulation. In this area, 
anti-nociceptive response is increased by the 
GAB A neurotransmission [11]. In particular, 
there is evidence that GABAa receptors 
modulate the nociceptive threshold affecting 
the noradrenergic bulbo-spinal projections 
from the insular cortex to the locus coeruleus, 
and GABAb receptors modulate the 
projections from cortex to amygdala 

Is the neuropathic pain a complete disease and 
not only the result of an other syndrome or 
injury? Interesting, newer molecular studies 
support this idea. Changes in DNA expression 
in the neuropathic pain syndrome have been 
observed. In response to peripheral noxious 
stimuli, dorsal horn neurons over-express the 
immediate early genes encoding transcription 
factors, such as c-jun and c-fos. These genes 
could be involved in cell death induction via a 
long-lasting cascade of transcriptional 
processes [12] . Indeed, the apoptotic genes 
mRNA expression levels of the bcl-2 cell 
death-associated family in the lumbar dorsal 
horn of the spinal cord of neuropathic rats are 
modified by peripheral nerve injury [13] . 

Following nerve injury, the afferent neurons 
(injured sensory neurons and their uninjured 
neighbours) close to the site of the injury 
increase their level of firing. This massive 
activity is called ectopic discharge, and it has 
also been proven in humans with neuropathic 
pain [14] . Altered expression of several types of 
sodium channels is responsible for the ectopic 

Copyright © Journal of Stem cells and Regenerative medicine. All rights reserved 
JSRM/ 003010200002/Nov 14, 2007. 

JSRM/Vol3 No.l, 2007; p 2 -11 


Vol3 Issuel 

Journal of Stem Cells & Regenerative Medicine 

firing after nerve injury, such as the voltage- 
gated sodium channels [15 ' 16] . The mechanisms 
responsible for the changes in the channel 
expression are not yet clear. Involvement of 
the neurotrophin (such as NGF, GDNF) 
supply has been suggested as a possibility . 

and mechanical allodynia in a pain model, the 
chronic constriction injury of the sciatic nerve, 
if administered locally on the site of nerve 



The calcium channels may also contribute to 
the induction of hyperalgesia and allodynia 


After peripheral nerve injury, sprouting of 
collateral fibres from sensory axons in the skin 
into denervated areas has been observed [19>20] . 
Neurotrophic factors and several cytokines, 
such as interleukin-1 (IL-1) and tumour 
necrosis factor-alpha (TNF-alpha), may be 
involved in the sprouting formation and in 
pathophysiology of neuropathic pain [21,22] . 

Classical pharmacological treatment 

Pain has a very complex nature. Nowadays 
there are not drugs for the neuropathic pain 
treatment acting in a complete and definitive 


Currently, lidocaine, lamotrigine, 

acetaminophen, dextromethorphan, 
carbamazepine, gabapentin, valproic acid, 
opioid analgesics, tramadol hydrochloride, and 
tricyclic antidepressants are used for the 
classical pharmacological treatment of 
neuropathic pain. 

Clinical research is studying new direct-acting 
compounds to sodium and calcium channels 
since the ability of these channels to contribute 
to the development of neuronal 
hyperexcitability and the production of pain- 
associated behaviour. Lidocaine, a sodium 
channel blocker, is effective in the pain relief 
1231 , however, the available blockers are not 
specific between the several types of sodium 
channels. A private company is developing a 
new sodium channel blocker, Ralfinamide, for 
the potential treatment of neuropathic pain [24 ' 


More interesting, reduction of 

Specific antagonists for the neuronal calcium 
channel are able to reduce heat hyperalgesia 

Copyright © Journal of Stem cells and Regenerative medicine. All rights reserved 
JSRM/ 003010200002/Nov 14, 2007. 

neuropathic pain associated with spinal cord 
injury in humans has been shown with 
intrathecal ziconotide, a marine-derived 
peptide [26] . 

Calcium flux is decreased by activation of the 
cannabinoid receptor subtype 1 . The synthetic 
cannabinoid CB1 receptor agonist Win 
55,212-2 decreases neuropathic pain 
behaviour, such as thermal hyperalgesia and 
mechanical allodynia [27] . 

As mentioned above, the main nociceptive 
neurotransmitter is glutamate. Inflammation 
and central sensitization are also controlled by 
NMD A glutamate receptors. NMD A receptor 
antagonists are able to attenuate neuropathic 
pain. Indeed, the NMDA receptor antagonist 
MK-801 has a potent anti-nociceptive effect 
[28, 29, 30]^ but du£ tQ - ts jjjgjj tox j c p r0 p er ties 

and low safety margins it is not available for 
clinical use on human patients. Nevertheless, 
amantadine, dextromethorphan, ketamine, and 
memantine are commercially available 
NMDA-receptor antagonists. The opioids 
methadone, dextropropoxyphene and 
ketobemidone are also NMDA-antagonists, as 
well as the triciclic antidepressant amitriptiline 
[3i, 32] NMDA-receptor antagonists in 
combination with opioids might represent a 
new class of analgesic and might have 
potential as a co-analgesic; NMDA-receptor 
antagonists help to enhance development of 
tolerance to opioid analgesics [33] . 

In pain transmission, glutamate activates also 
group I metabotropic receptors (mGluRs). 
Peripheral and central mGluR5 receptors are 
responsible of the nociceptive transmission 
observed during post-operative pain [34] . 
MPEP, the potent and selective antagonist for 
metabotropic glutamate receptor subtype 5 
(mGlu5), is able to prevent the development of 
thermal hyperalgesia, transiently reduce 
mechanical hyperalgesia in neuropathic rats, 
and prevent the over-expression of pro- 
apoptotic genes in dorsal horn spinal cord 

JSRM/Vol3 No.l, 2007; p 2 -11 


Vol3 Issuel 

Journal of Stem Cells & Regenerative Medicine 

neurons . This subtype of metabotropic 
glutamate receptors could represent the 
prototype of new potential drugs in pain 
treatment; however, due to the complex role of 
glutamate in the nervous central system, 
blockade of glutamate receptors is associated 
with several side effects. 

The typical mu-opioid analgesics, such as 
morphine, can be relatively ineffective in 
treating neuropathic pain since different 
opioids can produce analgesia by affecting 
different pain pathways [35] . 

responsiveness of dorsal horn sensory neurons 
and to hyperalgesia and allodynia [16 ' 41 ' 42 ' 43 ' u ' 
45 ' 461 . Gene silencing by the use of antisense 
oligonucleotides, a novel molecular 
pharmacological approach, causes a decrease 
in pain-related behaviour. 

Nicotinic receptors, P2X receptors, 5-HT1A 
receptors, NMDA glutamate receptors and 
opioid receptors have been successfully used 
as target for antisense knock-downing 
strategy, showing a decrease in nociceptive 
behaviour [47 ' 48 ' 49 ' 50 ' 51 ' 52] . 

Likely, the optimal classical drugs in the 
treatment of neuropathic pain are the 
anticonvulsant gabapentin, and its successor 
pregabalin [36 ' 37 ' 38 ' 39] . They are able to 
decrease the hyperexcitability of dorsal horn 
neurons induced by tissue injury, but their 
mechanism of action is still unclear. 
Interesting, they have only an effect in a 
condition of sensitization of a nociceptive 

Molecular methods for neuropatl 

Newer molecular methods, such as gene 
therapy and viral vector for the delivery of 
biologic anti-nociceptive molecules, could 
represent a novel therapeutic approach to the 
neuropathic pain treatment [40] . 

Following peripheral nerve injury, spinal re- 
organization and changes in the excitatory or 
inhibitory pathways controlling neuropathic 
pain development are correlated with altered 
gene expression. Novel molecular 
pharmacological strategy is directed toward 
the control of the gene up- or down-regulation. 
Antisense knock-down strategy could 
represent a novel approach to the neuropathic 
pain therapy in the nearest future. As next 
step, antisense research has to elucidate the 
pharmacodynamics, pharmacokinetics and 
distributions of antisense oligonucleotides. 

Among the genes showing altered expression 
in neuropathic pain, several sodium and 
calcium channels contribute to the hyper- 

Copyright © Journal of Stem cells and Regenerative medicine. All 
JSRM/ 003010200002/Nov 14, 2007. 

Immediate early genes, such as c-fos, are over- 
expressed in dorsal horn neurons of the spinal 
cord after peripheral nerve injury. Also in this 
case, intrathecal administration into the 
lumbar region L1-L5 of c-fos antisense 
oligonucleotides has shown a role played by 
the c-fos gene in neuropathic pain [53] . 

Viral vector technology to delivery anti- 
nociceptive molecules could represent a novel 
therapeutic strategy. Dorsal root ganglion 
neurons transduced with replication- 
incompetent herpes simplex virus (HSV-) 
based vector, encoding the GAD67 isoform of 
human glutamic acid decarboxylase, are able 
to produce GAD and release GABA, reducing 
neuropathic pain following a spinal cord 
injury [54] . Constitutive GABA expression via 
recombinant adeno-associated virus producing 
GAD65 attenuates neuropathic pain [55] . It has 
been demonstrated that virus encoding human 
pre-proenkephalin (hPPE) are able to decrease 
the activation-levels of nociceptors by 
capsaicin treatment in mice and macaques [56] . 

Coupling antisense knock-down and viral 
vector technology is showing promising 
results. Virus delivering antisense cDNA 
versus calcitonin gene-related peptide 
precursor (ACGRP) decreases C-fiber 
hyperalgesia due to the application of 
capsaicin on the skin in mice [561 . 

Potentially, all the molecules, such as 
neurotrophines, having nociceptive effects 
could be delivered by adenovirus. Candidate 
gene products include directly analgesic 

its reserved 

JSRM/Vol3 No.l, 2007; p 2 -11 


Vol3 Issuel 

Journal of Stem Cells & Regenerative Medicine 

molecules, as well as molecules that are able 
to interfere with pain-associated biochemical 
changes in pain pathways. Recombinant 
adenovirus encoding NT-3, BDNF, GDNF, or 

Semaphorin3A into animal models of 
neuropathy showed good results for 

■ • ,• r [57, 58, 59, 60, 61, 62] 

neuropathic pain relief L J . 
Intrathecal delivery of the adenovirus- 
mediated IL-2 gene has a relatively long anti- 
nociceptive effect [63] . 

Non-invasive gene delivery systems could be 
usefully used for targeting peripheral nervous 
system pathologies. Subcutaneous peripheral 
injection of plasmid DNA complexed with a 
non-viral cationized gelatin (CG) vector led to 
transgene expression in rat lumbar dorsal root 
ganglia [64] . 

Stem cell therapy 

Nowadays, stem cell therapy represents the 
great promise for the future of molecular 
medicine. Several diseases can be slowed or 
even blocked by stem cell transplantation. 
Stem cells could be neuroprotective in a 
variety of nervous system injury models. As 
neurodegenerative disease, also neuropathic 
pain undergoes to stem cell therapy [40] , even if 
the state of the art is still poor of basic and 
clinical research. 

Marrow mononuclear cells containing mixed 
stem cell populations have been intravenous 
used in neuropathic rats showing recovery 
from pain [65] . 

Stem cell implantation could be a possible 
solution for spinal cord injury. Stem cells have 
the ability to incorporate into spinal cord, 
differentiate, and to improve locomotor 


Despite ethical problems, it has been 
demonstrated that human embryonic neural 
stem cells can promote functional 
corticospinal axons regeneration and synapse 
reformation in the injured spinal cord of rats. 
The action is mainly through the nutritional 
effect of the stem cells on the spinal cord. 

Copyright © Journal of Stem cells and Regenerative medicine. All 
JSRM/ 003010200002/Nov 14, 2007. 

Transplanted cells were found to migrate into 
the lesion, but not scatter along the route of 
axon grows. The cells differentiated into 
astrocytes or oligodendrocytes, but not into the 
neurons after transplantation [67] . 

Spinal progenitor cells intrathecally 
transplanted in neuropathic rats are able to 
alleviate neuropathic pain [ 68 ]. Murine neural 
stem cells (NSCs) homografted onto the 
injured spinal cord improved motor behaviour 


How do stem cells work? Stem cells 
transplanted following spinal cord injury are 
able to reduce allodynia and improve 
functional recovery if they produce more 
oligodendrocytes than astrocytes [70] . 
Serotonergic neural precursor cell grafts are 
able to reduce hyperexcitability caused by 
spinal injury [71] . Neuropathic pain causes a 
decrease in the number and activity of 
GABAergic neurons, the spinal progenitor 
cells show glutamic acid decarboxylase 
immunocompetence, in this way they can 
supply the decreased GAB A profile [70 ' 721 . 

Is the stem cell differentiation the key for the 
pain care? Or do they provide several 
molecules with analgesic action? Indeed, 
using of genetically engineered stem cells 
expressing anti-nociceptive molecules or 
trophic factors seems to be an useful tool in 
neuropathic pain relief. Stem cells could be 
used as biologic "minipumps" to chronically 
deliver anti-nociceptive molecules close to the 
pain processing centers or the sites of injury 

[73, 74] 

Besides genetic engineering, stem cells 
applied to the site of the injury could provide 
trophic factors directly in situ, by this way 
acting as anti-nociceptive drug. 

Among the stem cell population, 
mesenchymal stem cells (MSCs) rise probably 
best potential good results in pain-care 
research. These cells are a population of 
progenitor cells of mesodermal origin found in 
the bone marrow of adults, giving rise to 
skeletal muscle cells, blood, fat, vascular and 

rights reserved 

JSRM/Vol3 No.l, 2007; p 2 -11 


Vol3 Issuel 

Journal of Stem Cells & Regenerative Medicine 

urogenital systems, and to connective tissues 
throughout the body [75,76] . MSCs show a high 
expansion potential, genetic stability, stable 
phenotype, can be easily collected and shipped 
from the laboratory to the bedside and are 
compatible with different delivery methods 
and formulations [77] . In addition, MSCs have 
two other extraordinary characteristics: they 
are able to migrate to sites of tissue injury and 
have strong immunosuppressive properties 
that can be exploited for successful autologous 
as well as heterologous transplantations I78] . 
Besides, MSCs are capable of differentiating 
into neurons and astrocytes in vitro and in 
vivo [79] . Recently, MSC injection has shown 
good results for amyotrophic lateral sclerosis 
treatment in human [80] . They are able to 
improve neurological deficits and to promote 
neuronal networks with functional synaptic 
transmission when transplanted into animal 
models of neurological disorders [81] . 

MSCs have been observed to migrate to the 
injured tissues and mediate functional 
recovery following brain, spinal cord and 
peripheral nerve lesions, suggesting that 
MSCs could modulate pain generation after 
sciatic nerve constriction [821 , although the 
underlying mechanisms by which MSCs exert 
their actions on pain behavior is still to be 

We are currently studying the use of human 
mesenchymal stem cells (hMSCs) for 
neuropathic pain treatment in rodents. hMSCs 
micro-injected into specific nuclei involved in 
pain processing were able to completely 
abolish pain-like behaviour in neuropathic 
mice (Siniscalco, 2007, unpublished data). 

Recently, Dr Stephen Richardson of the 
University of Manchester has developed, 
under patent, a cell-based tissue engineering 
approach to regenerate the intervertebral disc 
at the affected level in the low back pain 
( This is 
achieved through the combination of the 
patients' own mesenchymal stem cells and a 
naturally occurring collagen gel that can be 
implanted through a minimally-invasive 
surgical technique. Hopefully, once implanted 

Copyright © Journal of Stem cells and Regenerative medicine. All 
JSRM/ 003010200002/Nov 14, 2007. 

the differentiated MSCs would produce a new 
tissue with the same properties as the original 
and would both treat the underlying cause of 
the disease and remove the painful symptoms. 


Neuropathic pain has a great impact on the 
quality of life, reducing human wellbeing. 
Management of chronic pain is very costly to 
the health care system. Since 75-150 million 
people in the United States have a chronic 
pain disorder [40] . The United States Congress 
has declared the present decade (2001-2010) 
as the "Decade of Pain Control and Research", 
making pain a national healthcare priority. 

Neuropathic pain involves several molecular 
pathways and is a very complex disease. It has 
an individual character, making its treatment 
extremely difficult. Currently, available 
treatments address the pain-symptoms using a 
combination of painkillers. None of these is 
ideal as they only treat the symptoms and 
temporal pain properties, not the cause, and 
limited long-term success. 

Novel molecular methods, such as antisense 
strategy, gene therapy, and virus therapy, are 
acting on the several mechanisms underlying 
the generation and propagation of pain. More 
recently, preliminary clinical evidence 
suggests that stem cell therapy could provide 
best results, this strategy could be the 
definitive pain-relief drug for the next future. 


1. Merskey H, Bogduk N. Classification of chronic pain. 
IASP press, Seattle, 1994. 

2. Siniscalco D, de Novellis V, Rossi F, Maione S. 
Neuropathic pain: is the end of suffering starting in the 
gene therapy. Curr Drug Targets. 2005; 6: 75-80. 

3. de Novellis V, Siniscalco D, Galderisi U, Fuccio C, 
Nolano M, Santoro L, Cascino A, Roth KA, Rossi F, 
Maione S. Blockade of glutamate mGlu5 receptors in a 
rat model of neuropathic pain prevents early over- 
expression of pro-apoptotic genes and morphological 
changes in dorsal horn lamina II. Neuropharmacology 
2004; 46: 468-479. 

its reserved 

JSRM/Vol3 No.l, 2007; p 2 -11 


Vol3 Issuel 

Journal of Stem Cells & Regenerative Medicine 

4. Bonica JJ. In Advances in Pain Research and Therapy. 
Raven Press, New York, 1970, ppl4 1-166. 

Ill and SNS gene expression in spinal sensory neurons. 
Neuroreport. 1997; 8: 2331-2335. 

5. Kandel E.R, Schwartz JH, Jessel TM. In Principles of 
Neural Science. McGraw-Hill, New York, 4th ed. 2000. 

6. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, 
symptoms, mechanisms and management. Lancet 1999; 

7. Coderre TJ, Katz J, Vaccarino AL, Melzack R. 
Contribution of central neuroplasticity to pathological 
pain: review of clinical and experimental evidence. Pain 
1993; 52: 259-285. 

8. Mendell L.M. physiological properties of 
unmyelinated fiber projection to the spinal cord. Exp. 
Neurol. 1996;16: 316-332. 

9. Doubell TP, Mannion RJ, Woolf CJ. In Textbook of 
Pain. Churchill Livingstone, London, 4th ed. 1999, 

10. Hua XY, Chen P, Yaksh TL. Inhibition of spinal 
protein kinase C reduces nerve injury-induced tactile 
allodynia in neuropathic rats. Neurosci Lett.. 1999; 276: 

1 1 . Jasmin L, Rabkin SD, Granato A, Boudah A, Ohara 
PT. Analgesia and hyperalgesia from GABA-mediated 
modulation of the cerebral cortex. Nature 2003; 424: 

12. Zimmermann M. Pathobiology of neuropathic pain. 
Eur J Pharmacol. 2001 ; 429: 23-37. 

13. Maione S, Siniscalco D, Galderisi U, de Novellis V, 
Uliano R, Di Bernardo G, Berrino L, Cascino A, Rossi F, 
Apoptotic genes expression in the lumbar dorsal horn in 
a model neuropathic pain in rat. Neuroreport.. 2002; 13: 

14. Wall PD, Gutnick M. Ongoing activity in peripheral 
nerves: the physiology and pharmacology of impulses 
originating from a neuroma. Exp Neurol. 1974; 43: 580- 

15. Waxman SG, Kocsis JD, Black JA. Type III sodium 
channel mRNA is expressed in embryonic but not adult 
spinal sensory neurons, and is reexpressed following 
axotomy. J Neurophysiol. 1994; 72: 466-470. 

16. Cervero F, Laird JMA. Role of ion channels in 
mechanisms controlling gastrointestinal pain pathways. 
Curr Opin Pharmacol. 2003; 3: 608-612. 

18. Xiao WH, Bennett GJ. Synthetic omega- 
conopeptides applied to the site of nerve injury suppress 
neuropathic pains in rats. J Pharmacol Exp Ther. 1995; 
274: 666-672. 

19. Amir R, Devor M. Chemically mediated cross- 
excitation in rat dorsal root ganglia. J Neurosci. 1996;16: 

20. Ro L, Chen S, Tang L, Chang H. Local application of 
anti-NGF blocks the collateral sprouting in rats 
following chronic constriction injury of the sciatic nerve. 
Neurosci Lett.. 1996; 218: 87-90. 

21. Sorkin LS and Doom CM. Epineurial application of 
TNF elicits an acute mechanical hyperalgesia in the 
awake rat. J Peripher Nerv Syst. 2000; 5: 96-100. 

22. Ignatowski TA, Covey WC, Knight PR, Severin CM, 
Nickola TJ, Spengler RN. Brain-derived TNFalpha 
mediates neuropathic pain. Brain Res. 1999; 841: 70-77. 

23. Bach FW, Jensen TS, Kastrup J, Stigsby B, Dejgard 
A. The effect of intravenous lidocaine on nociceptive 
processing in diabetic neuropathy. Pain 1990; 40: 29-34. 

24. Cattabeni F. Ralfinamide.Newron Pharmaceuticals. I 
Drugs. 2004; 7: 935-939. 

25. Yamane H. de Groat WC, Sculptoreanu A. Effects of 
ralfinamide, a Na+ channel blocker, on firing properties 
of nociceptive dorsal root ganglion neurons of adult rats. 
Exp Neuro. 2007;208: 63-72. 

26. Saulino M. Successful reduction of neuropathic pain 
associated with spinal cord injury via of a combination 
of intrathecal hydromorphone and ziconotide: a case 
report. Spinal Cord 2007; 45: 749-52. 

27. Pertwee R.G. Pharmacology of cannabinoid CB1 and 
CB2 receptors. Pharmacol Ther, 1997; 74: 129-180. 

28. Davar G, Hama A, Deykin A, Vos B, Maciewicz R. 
MK-801 blocks the development of thermal hyperalgesia 
in a rat model of experimental painful neuropathy. Brain 
Res. 1991;553:327-330. 

29. Mao J, Price DD, Mayer DJ, Lu J, Hayes RL. 
Intrathecal MK-801 and local nerve anesthesia 
synergistically reduce nociceptive behaviors in rats with 
experimental peripheral mononeuropathy. Brain 
Res. 1992; 576: 254-262. 

17. Black JA, Langworthy K, Hinson AW, Dib Hajj SD, 
Waxman SG. NGF has opposing effects on Na+ channel 

30. Sotgiu ML, Biella G. Differential effects of MK-801, 
a N-methyl-D-aspartate non-competitive antagonist, on 

Copyright © Journal of Stem cells and Regenerative medicine. All rights reserved 
JSRM/ 003010200002/Nov 14, 2007. 

JSRM/Vol3 No.l, 2007; p 2 -11 


Vol3 Issuel 

Journal of Stem Cells & Regenerative Medicine 

the dorsal horn neuron hyperactivity and 
hyperexcitability in neuropathic rats. Neurosci Lett.. 

31. Rabben T, Skjelbred P, Oye I. Prolonged analgesic 
effect of ketamine, an N-methyl-D-aspartate receptor 
inhibitor, in patients with chronic pain. J Pharmacol Exp 
Ther. 1999; 289: 1060-1066. 

32. Jasik M. Therapy of diabetic neuropathy. Przegl Lek. 
2003; 60: 167-169. 

33. Hewitt DJ. The use of NMD A-receptor antagonists in 
the treatment of chronic pain. Clin J Pain. 2000; 16: 73- 

34. Zhu CZ, Hsieh G, Ei-Kouhen O, Wilson SG, Mikusa 
JP, Hollingsworth PR, Chang R, Moreland RB, Brioni J, 
Decker MW, Honore P. Role of central and peripheral 
mGluR5 receptors in post-operative pain in rats. Pain 
2005; 114(1-2): 195-202. 

35. Likar R., Sittl R. Transdermal buprenorphine for 
treating nociceptive and neuropathic pain: four case 
studies. Anesth Analg. 2005; 100: 781-785. 

36. Maneuf YP, Gonzalez MI, Sutton KS, Chung FZ, 
Pinnock RD, Lee K. Cellular and molecular action of the 
putative GABA-mimetic, gabapentin. Cell Mol Life Sci. 
2003; 60: 742-750. 

37. Johnson S, Johnson FN, Johnson RD, Armer ML. In 
Reviews in Contemporary Pharmacotherapy. Marius 
Press, Carnforth; 200, ppl25-211. 

38. Urban MO, Ren K, Park KT, Campbell B, Anker N, 
Stearns B, Aiyar J, Belley M, Cohen C, Bristow L. 
Comparison of the antinociceptive profiles of gabapentin 
and 3-methylgabapentin in rat models of acute and 
persistent pain: implications for mechanism of action. J 
Pharmacol Exp Ther. 2005; 313: 1209-1216. 

39. Dahl JB, Mathiesen O, Moiniche S. 'Protective 
premedication': an option with gabapentin and related 
drugs? A review of gabapentin and pregabalin in in the 
treatment of post-operative pain. Acta Anaesthesiol 
Scand. 2004; 48: 1130-1136. 

40. Siniscalco D, Rossi F, Maione S. Molecular 
approaches for neuropathic pain treatment. Curr Med 
Chem. 2007; 14: 1783-1787. 

41. Dib-Hajj SD, Fjell J, Cummins TR, Zheng Z, Fried 
K, LaMotte R, Black JA, Waxman SG. Plasticity of 
sodium channel expression in DRG neurons in the 
chronic constriction injury model of neuropathic pain. 
Pain 1999; 83:591-600. 

42. Devor M, Keller CH, Deerinck TJ, Levinson SR, 
Ellisman MH. Na+ channel accumulation on axolemma 
of afferent endings in nerve end neuromas in 
Apteronotus. Neurosci Lett.. 1989; 102: 149-154. 

43. Hains BC, Saab CY, Klein JP, Craner MJ, Waxman 
SG. Altered sodium channel expression in second-order 
spinal sensory neurons contributes to pain after 
peripheral nerve injury. J Neurosci. 2004; 24: 4832- 

44. Lai J, Gold MS, Kim CS, Bian D, Ossipov MH, 
Hunter JC, Porreca F. Inhibition of neuropathic pain by 
decreased expression of the tetrodotoxin-resistant 
sodium channel, NaV1.8. Pain 2002; 95: 143-152. 

45. Valder CR, Liu JJ, Song YH, Luo ZD. Coupling 
gene chip analyses and rat genetic variances in 
identifying potential target genes that may contribute to 
neuropathic allodynia development. J Neurochem. 2003; 
87: 560-573. 

46. Li CY, Song YH, Higuera ES, Luo ZD. Spinal dorsal 
horn calcium channel alpha2delta-l subunit upregulation 
contributes to peripheral nerve injury-induced tactile 
allodynia. J Neurosci. 2004; 24: 8494-8499. 

47. Vincler MA, Eisenach JC. Knock down of the alpha 
5 nicotinic acetylcholine receptor in spinal nerve-ligated 
rats alleviates mechanical allodynia. Pharmacol Biochem 
Behav. 2005; 80: 135-143. 

48. Garry MG, Malik S, Yu J, Davis MA, Yang J. Knock 
down of spinal NMDA receptors reduces NMDA and 
formalin evoked behaviors in rat. Neuroreport. 2000; 11: 

49. Przewlocka B, Sieja A, Starowicz K, Maj M, Bilecki 
W, Przewlocki R. Knockdown of spinal opioid receptors 
by antisense targeting beta-arrestin reduces morphine 
tolerance and allodynia in rat. Neurosci Lett. 2002; 325: 

50. Kennedy C, Assis TS, Currie AJ, Rowan EG. 
Crossing the pain barrier: P2 receptors as targets for 
novel analgesics. J Physiol. 2003; 553: 683-694. 51. 
Honore P, Kage K, Mikusa J, Watt AT, Johnston JF, 
Wyatt JR, Faltynek CR, Jarvis MF, Lynch K. Analgesic 
profile of intrathecal P2X(3) antisense oligonucleotide 
treatment in chronic inflammatory and neuropathic pain 
states in rats. Pain 2002; 99: 1 1-19. 

52. Hernandez A, Constandil L, Laurido C, Pelissier T, 
Marchand F, Ardid D, Alloui A, Eschalier A, Soto- 
Moyano R. Venlafaxine-induced depression of wind-up 
activity in mononeuropathic rats is potentiated by 
inhibition of brain 5-HT1A receptor expression in vivo. 
Int J Neurosci. 2004; 1 14: 229-242. 

Copyright © Journal of Stem cells and Regenerative medicine. All rights reserved 
JSRM/ 003010200002/Nov 14, 2007. 

JSRM/Vol3 No.l, 2007; p 2 -11 


Vol3 Issuel 

53. Huang W, Simpson RK. Antisense of c-fos gene 
attenuates Fos expression in the spinal cord induced by 
unilateral constriction of the sciatic nerve in the rat. Jr. 
Neurosci Lett.. 1999; 263: 61-64. 

Journal of Stem Cells & Regenerative Medicine 

64. Thakor D, Spigelman I, Tabata Y, Nishimura I. 
Subcutaneous peripheral injection of cationized 
gelatin/DNA polyplexes as a platform for non-viral gene 
transfer to sensory neurons. Mol Ther. 2007 15:2124-31. 

54. Liu J, Wolfe D, Hao S, Huang S, Glorioso JC, Mata 
M, Fink DJ. Peripherally delivered glutamic acid 
decarboxylase gene therapy for spinal cord injury pain. 
Mol Ther .2004; 10: 57-66. 

65. Klass M, Gavrikov V, Drury D, Stewart B, Hunter S, 
Denson DD, Hord A, Csete M. Intravenous mononuclear 
marrow cells reverse neuropathic pain from experimental 
mononeuropathy. Anesth Anal. 2007; 104: 944-948. 

55. Lee B, Kim J, Kim SJ, Lee H, Chang JW. 
Constitutive GABA expression via a recombinant adeno- 

virus consistently attenuates neuropathic pain. Biochem 
Biophys Res Commun. 2007; 357: 971-976. 

66. Schultz SS. Adult stem cell application in spinal cord 
injury. Curr Drug Targets. 2005; 6: 63-73. 

67. Liang P, Jin LH, Liang T, Liu EZ, Zhao SG. Human 
neural stem cells promote corticospinal axons 
regeneration and synapse reformation in injured spinal 
cord of rats.Chin Med J. 2006; 119: 1331-1338. 

56. Wilson SP, Yeomans DC. Virally mediated delivery 
of enkephalin and other neuropeptide transgenes in 
experimental pain models. Ann NY Acad Sci. 2002; 971: 

57. Yeomans DC, Lu Y, Laurito CE, Peters MC, Vota- 
Vellis G, Wilson SP, Pappas GD. Recombinant herpes 
vector-mediated analgesia in a primate model of 
hyperalgesia. Mol Ther. 2006; 13: 589-597. 

58. Yeomans DC, Jones T, Laurito CE, Lu Y, Wilson 
SP. Reversal of ongoing thermal hyperalgesia in mice by 
a recombinant herpesvirus that encodes human 
preproenkephalin. Mol Ther. 2004; 9: 24-29. 

68. Lin C.R, Wu PC, Shih HC, Cheng JT, Lu CY, Chou 
AK, Yang LC. Intrathecal Spinal Progenitor Cell 
Transplantation for the Treatment of Neuropathic Pain. 
Cell Transplant. 2002; 1 1 : 17-24. 

69. Pallini R, Vitiani LR, Bez A, Casalbore P, Facchiano 
F, Di Giorgi Gerevini V, Falchetti ML, Fernandez E, 
Maira G, Peschle C, Parati E. Homologous 
transplantation of neural stem cells to the injured spinal 
cord of mice. Neurosurgery 2005; 57: 1014-1025. 

70. Klein S, Svendsen CN. Stem cells in the injured 
spinal cord: reducing the pain and increasing the gain. 
Nature Neurosci. 2005; 8: 259-260. 

59. Tai MH, Cheng H, Wu JP, Liu YL, Lin PR, Kuo JS, 
Tseng CJ, Tzeng SF. Gene transfer of glial cell line- 
derived neurotrophic factor promotes functional recovery 
following spinal cord contusion. Exp Neurol. 2003; 183: 

60. Pradat PF, Kennel P, Naimi-Sadaoui S, Finiels F, 
Orsini C, Revah F, Delaere P, Mallet. J. Continuous 
delivery of neurotrophin 3 by gene therapy has a 
neuroprotective effect in experimental models of diabetic 
and acrylamide neuropathies. Hum Gene Ther. 2001; 12: 

61. Eaton MJ, Blits B, Ruitenberg MJ, Verhaagen J, 
Oudega M. Amelioration of chronic neuropathic pain 
after partial nerve injury by adeno-associated viral 
(AAV) vector-mediated over-expression of BDNF in the 
rat spinal cord. Gene Ther. 2002; 9: 1387-1395. 

62. Tang XQ, Tanelian DL, Smith GM. Semaphorin3A 
inhibits nerve growth factor-induced sprouting of 
nociceptive afferents in adult rat spinal cord. J Neurosci. 
2004; 24: 819-827. 

63. Yao MZ, Gu JF, Wang JH, Sun LY, Liu H, Liu XY. 
Adenovirus-mediated interleukin-2 gene therapy of 
nociception. Gene Ther. 2003; 10: 1392-1399. 

71. Hains BC, Johnson KM, Eaton MJ, Willis WD, 
Hulsebosch CE. Serotonergic neural precursor cell grafts 
attenuate bilateral hyperexcitability of dorsal horn 
neurons after spinal hemisection in rat. Neuroscience 
2003; 116: 1097-1110. 

72. Moore KA, Kohno T, Karchewski LA, Scholz J, 
Baba H, Woolf CJ. Partial peripheral nerve injury 
promotes a selective loss of GABAergic inhibition in the 
superficial dorsal horn of the spinal cord. J Neurosci. 
2002; 22: 6724-6731. 

73. Eaton MJ, Plunkett JA, Martinez MA, Lopez T, 
Karmally S, Cejas P, Whittemore SR. Transplants of 
neuronal cells bioengineered to synthesize GABA 
alleviate chronic neuropathic pain. Cell Transplant. 
1999; 8: 87-101. 

74. Cejas PJ, Martinez M, Karmally S, McKillop M, 
McKillop J, Plunkett JA, Oudega M, Eaton MJ. Lumbar 
transplant of neurons genetically modified to secrete 
brain-derived neurotrophic factor attenuates allodynia 
and hyperalgesia after sciatic nerve constriction. Pain 
2000; 86: 195-210. 

75. Beyer Nardi N, da Silva Meirelles L. Mesenchymal 
stem cells: isolation, in vitro expansion and 

Copyright © Journal of Stem cells and Regenerative medicine. All rights reserved 
JSRM/ 003010200002/Nov 14, 2007. 

JSRM/Vol3 No.l, 2007; p 2 -11 


Vol3 Issuel 

characterization. Handb Exp Pharmacol. 2006; 174: 

Journal of Stem Cells & Regenerative Medicine 

76. Sethe S, Scutt A, Stolzing A. Aging of mesenchymal 
stem cells. Ageing Res Rev, 2006; 5: 91-116. 

77. Giordano A, Galderisi U, Marino IR. From the 
laboratory bench to the patient's bedside: an update on 
clinical trials with mesenchymal stem cells. J Cell 
Physiol. 2007; 211: 27-35. 

78. Le Blanc K, Pittenger M. Mesenchymal stem cells: 
progress toward promise.Cytotherapy 2005; 7: 36-45. 

79. Jori FP, Napolitano MA, Melone MA, Cipollaro M, 
Cascino A, Altucci L, Peluso G, Giordano A, Galderisi 
U Molecular pathways involved in neural in vitro 
differentiation of marrow stromal stem cells. J Cell 
Biochem. 2005; 94: 645-655. 

80. Mazzini L, Mareschi K, Ferrero I, Vassallo E, Oliveri 
G, Nasuelli N, Oggioni GD, Testa L, Fagioli F. Stem cell 
treatment in Amyotrophic Lateral Sclerosis. J Cell 
Biochem. 2005; 94: 645-55. 

81. Bae JS, Han HS, Youn DH, Carter JE, Modo M, 
Schuchman EH, Jin HK Bone marrow-derived 
mesenchymal stem cells promote neuronal networks with 
functional synaptic transmission after transplantation 
into mice with neurodegeneration. Stem Cells 2007; 

82. Musolino PL, Coronel MF, Hokfelt T, Villar MJ. 
Bone marrow stromal cells induce changes in pain 
behavior after sciatic nerve constriction. Neurosci Lett.. 


Copyright © Journal of Stem cells and Regenerative medicine. All rights reserved 
JSRM/ 003010200002/Nov 14, 2007. 

JSRM/Vol3 No.l, 2007; p 2 -11 

- 11- 

Vol3 Issuel